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Acute Renal Failure Related to Rhabdomyolysis: Pathophysiology, Diagnosis, and Collaborative Management.

Bywaters and Beall's description of rhabdomyolysis during World War II provided the first causal association between acute renal failure (ARF) and rhabdomyolysis (Bonventre, Shah, Walker, & Humphreys, 1995; Knochel, 1998; Zager, 1996). Rhabdomyolysis is referred to as pigment nephropathy (Knochel, 1998), myoglobinuric ARF, or pigment-induced ARF (Bonventre et al., 1995). Rhabdomyolysis is a syndrome that results from damage to skeletal muscle that leads to the appearance of myoglobin in the circulation. Myoglobin is filtered by the glomeruli causing elevated levels of urinary myoglobin that can lead to ARF (Visweswaran & Guntupalli, 1999). Although the list of conditions leading to rhabdomyolysis is lengthy, the common theme that relates all the causes is an interruption of normal cell metabolism resulting in muscle cell lysis, which leads to release of intracellular contents into the circulation. Muscle ischemia, a frequent cause, results from interruption of blood flow (absolute) or from muscle metabolism that exceeds the ability of its blood supply to provide oxygen (relative) (Bonventre et al., 1995). The most common causes of rhabdomyolysis are prodigious exercise, trauma, and alcohol abuse (Bonventre et al., 1995; Holt et al., 1999; Lopez, Rojas, Gonzalez, & Terzic, 1995). While the precise mechanisms responsible for rhabdomyolysis are not fully understood, it is implicated as a major cause of ARF (Bonventre et al., 1995). Rhabdomyolysis is the etiology of 7-10% of all cases of ARF in the United States (Holt et al., 1999). Whether progression to ARF is due to misdiagnoses early in the course of the disorder is unclear.

While frequently classified as traumatic or nontraumatic, the causes of rhabdomyolysis are often multifactorial. Table 1 lists numerous causes of rhabdomyolysis. This article will focus on the pathophysiology, diagnosis, and collaborative management of exertional (nontraumatic) rhabdomyolysis that results in ARF. Each member of the health care team needs to be able to recognize the signs and symptoms for rapid diagnosis. Understanding the pathophysiology will prompt collaborative management.

Table 1

Causes of Rhabdomyolysis
Metabolic/Electrolytes:             Infections:

* Hypokalemia                       * Viral
* Hypophosphatemia                  * Bacterial
* Myopathies                        * Septicemia
* Inherited disorders of fatty
  acid metabolism
* Glycogen storage

Polymyositis                        Dermatomyositis

Neuroleptic malignant               Muscle exertion:
                                    * Physical
* Anesthesia                        * Secondary to convulsions
* Phenothiazines                      or heat injury
* MAO inhibitors

Extended periods of muscle          Extreme lithotomy position
pressure:                           for extended periods

* After allogenic bone
  marrow transplant
* Hyponatremia or correction
* Hypothyroidism
* Water intoxication
* Hypokalemia

Trauma:                             Status epilepticus

* Crush syndromes
* Pseudo-crush syndrome

Toxic muscle injury:                Drug induced:

* Alcohol induced                   * Crack-cocaine
* Tetanus                           * Heroin
* Snake venom                       * Amphetamine abuse
* Carbon monoxide

Hyperosmolality                     Burns

Repetitive muscle injury:           Drug overdoses:

* Bongo drumming                    * Theophylline and INH
* Torture                           * Lipid lowering agents
                                    * Any drug that leads to
                                      neuroleptic malignant

Carcinoma:                          Diabetes mellitus

Acute necrotizing myopathy          * ketoacidosis
of carcinoma


The pathophysiology of ARF related to rhabdomyolysis is complex and lack of understanding can lead to misdiagnosis (Star, 1998). The most common etiology of exertional rhabdomyolysis is strenuous physical exercise. Somatic muscle comprises approximately 40% of the total body mass. It is vulnerable to a wide variety of insults (Visweswaran & Guntupalli, 1999; Zager, 1996). The final result of these insults may lead to muscle cell lysis, or rhabdomyolysis, that results in the release of intracellular components, which are toxic in the systemic circulation (Bonventre et al., 1995; Zager, 1996).

While the conditions leading to exertional rhabdomyolysis have been only partially explained, the syndrome has been shown to develop in distinct stages (see Figure 1). The initiating event (stage) is postulated to result from mechanical muscle fiber injury induced by eccentric contractions when the muscle is in an elongated condition (Zager, 1996). An example of eccentric muscle contractions is either walking or running downhill (Knochel, 1998). These factors lead to excessive tensile stress that result in muscle fiber injury. Compromised muscle capillary blood flow, coupled with glycogen and creatine high-energy phosphate consumption, results in adenosine triphosphate (ATP) depletion. ATP is necessary for effective muscle contraction, relaxation, and maintenance of muscle cell homeostasis. Muscle necrosis resulting from ATP depletion causes profound disturbances in muscle cell ion homeostasis (Zager, 1996).


The ATP depletion is thought to either lead to or greatly contribute to the next stage, the calcium overload stage (Lopez et al., 1995). The depleted energy stores disrupt transport across the muscle cell membrane, which allows calcium to accumulate in the muscle cell (Knochel, 1998; Zager, 1996).

The autogenous phase, believed to be initiated by the influx of calcium, is characterized by phospholipase and protease activation along with mitochondrial dysfunction and free radical formation [e.g., superoxide (MATHEMATICAL EXPRESSION NOT REPRODUCIBLE IN ASCII) the hydroxyl radical [[OH.sup.-]], and hydrogen peroxide ([H.sub.2][0.sub.2])] that perpetuate muscle cell membrane injury. The outcome of the autogenous phase is muscle cell death and the release of large amounts of myoglobin into the circulation (Zager, 1996).

Myoglobin is a heme pigment, similar to hemoglobin, enclosed in a globin chain with a small molecular weight of 17,000 Daltons (17 kD), which allows it to be filtered through the glomeruli. Both hemoglobin and myoglobin are reabsorbed in the proximal tubules by endocytosis (ingestion by the cell) (Visweswaran & Guntupalli, 1999). In acidic media, such as that of lysosomes, the globin chain dissociates from the iron-containing ferrihemate portion of the molecule that interferes with a number of transport functions (Bonventre et al., 1995). Normally, once inside the cell, metabolism of the porphyrin ring yields free iron that is rapidly converted to ferritin (storage form of iron). However, in rhabdomyolysis, excessive amounts of the porphyrin ring are delivered to the proximal tubule cell, which overwhelms its ability to convert the free iron into ferritin (Visweswaran & Guntupalli, 1999). Ferrihemate transport out of the cell requires a sufficient amount of ATP. Yet, as mentioned earlier, there is a reduction in ATP stores, so ferrihemate accumulates and renal tubular cells become injured (Knochel, 1998). Since iron is a transitional metal, it has the ability to readily accept and donate electrons and has the capability of generating oxygen and nonoxygen free radicals that lead to oxidant stress and injury to the renal cell (Visweswaran & Guntupalli, 1999).

Clinical experience has shown that intravascular volume depletion, renal vasoconstriction, or exposure to nephrotoxins, in combination with the presence of myoglobin, can lead to myoglobinuric ARF. In the absence of these contributing factors, even with large loads of myoglobin as reflected by high serum concentrations of muscle enzymes, renal failure may not occur (Bonventre et al., 1995).

Although rare, rhabdomyolysis may occur when the serum potassium concentration falls in the setting of intense exercise. Nielsen and Mazzone (1999) report the primary mechanism responsible for exertional rhabdomyolysis secondary to hypokalemia is potassium release from contracting muscle cells resulting in vasodilatation of arterioles. If this potassium-mediated arteriolar dilatation fails, ischemia ensues. Austin and Linas (1995) posit that the potassium depletion from sweating usually occurs in hot climates during intense physical exercise. Persons may experience losses in excess of 30 mEq/day that contribute to potassium depletion.


While the diagnosis of rhabdomyolysis can be suspected from a thorough history and physical examination, it must be confirmed by laboratory testing. In differentiating ARF related to rhabdomyolysis, any disease that causes acute tubular necrosis (ATN) can be confused with rhabdomyolysis. In addition, renal pigment injury from hemoglobin resembles pigment injury from myoglobin, which illustrates the importance of laboratory testing (Visweswaran & Guntupalli, 1999). Exertional rhabdomyolysis frequently occurs in people who are not adequately conditioned before severe exertion (Bonventre et al., 1995). One type of exertional rhabdomyolysis, termed "white-collar rhabdomyolysis," is observed in people such as physicians, businessmen, and attorneys who participate in competitive sports without being adequately conditioned to keep pace with a conditioned athlete (Bonventre et al, 1995; Knochel, 1998).


Because most cases of exertional rhabdomyolysis will be encountered in the emergency department, the history needs to be very focused so appropriate treatment and referrals can be made. The most important determination to make is what the person was doing before the symptoms appeared. The majority of patients will have participated in some type of sporting event they were not adequately trained for or were fulfilling a required duty of the military (such as running an obstacle course). The next question to consider is the air temperature in which the exercise took place. Most patients will experience signs and symptoms after vigorous exercise in the middle of the day. The next questions relate to nutrition and hydration. Did the patient eat anything before exercising? Did they keep themselves hydrated during the precipitating event? While most patients will have eaten something earlier that day, the majority of patients will not have been adequately hydrated.

Physical Examination Muscular signs and symptoms.

The diagnosis of exertional rhabdomyolysis is suspected in any patient who presents with obvious muscle damage, usually in an extremity, that shows reddened overlying skin with local swelling and induration (Bonventre et al., 1995). While the symptoms can vary depending on the cause, the most common are muscle pain, weakness, tenderness, stiffness, and, occasionally, contractures (Gabow, Kaehny, & Kelleher, 1982). Paralysis or severe weakness may occur because of extensive necrosis or hyperkalemia (Knochel, 1998). Fifty percent of patients will present with symptoms that involve the thighs, calves, and lower back. Upon palpation, the affected muscles are tender (Gabow et al., 1982).

Laboratory data. Urine. The first clue for the presence of myoglobinuria is found in the urinalysis (UA) (Bonventre et al., 1995; Szewczyk, Ovadia, Abdullah, & Rabinovici, 1998). The urine may be dark in color, usually with an acid pH (see Table 2). The benzidine reagent will give a positive reaction for blood (usually 3+ to 4+), but microscopic examination of the urinary sediment fails to reveal any red blood cells or, at most, only a few [less than 5 per high power field (HPF)] (Bonventre et al., 1995). The fundamental difference between myoglobin and hemoglobin in the plasma is that hemoglobin saturates haptoglobin at a concentration of 100 mg/dl. Because the hemoglobin-haptoglobin complex is a large molecule, it is not filtered by the glomerulus and will not appear in the urine until the plasma haptoglobin has become saturated. In contrast, myoglobin has no specific binding protein, so any myoglobin entering the plasma is readily filtered by the glomerulus (Knochel, 1998). The characteristic urine sediment is brown debris and pigmented brown granular casts; renal tubular epithelial cells may also be present (Bonventre et al., 1995). In a patient with ARF, urine electrolytes serve as an indicator of the functional integrity of the renal tubules. The single most important test is the fractional excretion of sodium ([FE.sub.NA]). To calculate the [FE.sub.NA], the following formula is used:

(Urine [Na]/Plasma [Na] / (Urine [Cr]/Plasma [Cr) x 100 = [FE.sub.NA].

In patients with prerenal azotemia, the [FE.sub.NA] is [is less than] 1% and in ATN it is [is greater than] 1% (Toto, 1998). In rhabdomyolysis, the typical urine sodium concentration is elevated ([is greater than] 20 mEq/L) and the [FE.sub.NA] is greater than 1% (Bonventre et al., 1995).

Table 2
Urinalysis Findings

Color                         Dark (cola-colored)

pH                            Acidic

    Benzidine reagent         (3+ - 4+)
    Microscopy                (0 - [is less than] 5 RBCs per high
                              power field)

Sediment                      Pigmented brown granular casts
                              Renal tubular epithelial cells

Urinary sodium concentration  [is greater than] 20 mEq/L

FENA                          [is greater than] 1%

Note: [FE.sub.NA] = fractional excretion of sodium

Blood. Serum creatine kinase (CK). Abnormal blood chemistries, especially CK, confirm the presence of muscle injury and help define its extent (Bonventre et al., 1995; Knochel, 1998; Szewczyk et al., 1998). Initial serum CK of patients with myoglobinuric ARF is typically greater than 15,000 IU/L (see Table 3) and occasionally exceeds 70,000 IU/L (Bonventre et al., 1995). In extreme cases, the CK level may approach 3.0 million IU/L (Knochel, 1998). CK performs the reversible reaction of converting creatine phosphate and adenosine diphosphate to creatine and adenosine triphosphate. CK isoenzymes are three species of dimers with roughly 60 kD molecular weight, composed of combinations of two possible subunits (M, muscle; B, brain). CK-MM is found mostly in skeletal muscle, whereas CK-BB is found both in kidney and brain tissue. The myocardium has the highest concentration of CK-MB isoenzyme, but there is roughly four to five times more CK-MM isoenzyme than CK-MB isoenzyme. The serum CK-MM is the dominant isoform in skeletal muscle, making it the most sensitive test to confirm the diagnosis of rhabdomyolysis (Knochel, 1998; Szewczyk et al., 1998). Because CK-MM has a longer half-life than CK-MB, it will continue to be elevated even after CK-MB falls below detectable levels (Anonymous, 1997). CK peaks at 12 to 36 hours and has a half-life of about 48 hours, making detection of elevations possible several days after acute muscle injury (Bonventre et al., 1995; Knochel, 1998). To enhance the sensitivity of serum CK determinations, it is essential to exclude other sources of this enzyme, specifically with the measurement of the serum CK-MB. Although an elevated CK-MB fraction will not exclude rhabdomyolysis, because of concurrent heart and noncardiac muscle injury, it should be included in the laboratory workup of every patient suspected with rhabdomyolysis (Szewczyk et al., 1998). An elevated carbonic anhydrase III level, although rarely performed for the detection of rhabdomyolysis due to expense and difficulty, is a more specific marker than myoglobin and CK because it is not present in the myocardium (Syrjala, Zvuori, Huttunen, & Vaananen, 1990).

Table 3 Serum Lab Values in Adults
                         Normal value          In Rhabdomyolysis

CK                       M: 55-170 IU/L        [up arrow]
                         F: 30-135 IU/L
   CK-MM                 100%                  [up arrow]
BUN: Creatinine ratio    10:1                  Early: [down arrow]
                                               Late: [up arrow]
Anion gap                12 +/- 2              [up arrow]
Phosphorus               3.0 - 4.5 mg/dl       [up arrow]
Calcium                  9.0 - 10.5 mg/dl      [up arrow]
Uric acid                M: 2.1 - 8.5 mg/dl    [up arrow]
                         F: 2.0 - 6.6 mg/dl    [up arrow]
Albumin                  3.2 - 4.5 mg/dl       [down arrow]
Hematocrit               M: 42-52%             [down arrow]
                         F: 37-47%             [up arrow]
Potassium                3.5 - 5.0 mEq/L

Note: Values may differ depending upon the clinical laboratory used. CK=creatine kinase

Other enzymes. Elevated levels of other muscle enzymes such as aldolase, lactic dehydrogenase, and Transaminases are also frequently found. While these may be the first laboratory results to suggest the diagnosis, Szewczyk et al. (1998) and Knochel (1998) agree that these enzymes are nonspecific and provide no additional useful information.

BUN: Creatinine ratio. A transient elevation of serum creatinine that is disproportionate to the elevation of blood urea nitrogen (BUN) (normal BUN: creatinine ratio 10:1) is frequently seen in acute rhabdomyolysis Bonventre et al., 1995; Knochel, 1998). This is caused by creatine in skeletal muscle undergoing irreversible and nonenzymatic dehydration to form creatinine, which then diffuses into the circulation and is excreted by the kidneys (Bonventre et al., 1995; Knochel, 1998). Rhabdomyolysis causes the serum creatinine concentration to rise very sharply, narrowing the normal BUN to creatinine ratio to within five or less (Bonventre et al., 1995; Knochel, 1998). Later in the development of the course of the disease, catabolism of muscle protein leads to dramatic increases in urea production, so the BUN to creatinine ratio will rise to higher than normal levels (Bonventre et al., 1995).

Increased anion gap. The serum anion gap [Na.sup.+] - ([Cl.sup.-] + [MATHEMATICAL EXPRESSION NOT REPRODUCIBLE IN ASCII])] in patients with rhabdomyolysis that causes ARF is significantly higher than in other causes of ARE The anion gap is the difference between the measured cations and the measured anions. The anion gap is normally 12 +/- 2 mmol/liter. A high anion gap generally indicates an overproduction of organic acids in the serum or renal failure. These organic acids, along with elevated phosphates, contribute to the increased anion gap seen in rhabdomyolysis (Singer, 1998).

Hyperphosphatemia and hypocalcemia. Muscle damage leads to the breakdown of intracellular phosphate compounds and the release of large quantities of inorganic phosphorus resulting in hyperphosphatemia.

Hyperphosphatemia increases the calcium-phosphate product, and the damaged muscle serves as the site for deposition of calcium phosphate (Bonventre et al., 1995). Profound hypocalcemia ([is less than] 3.0 mg/dl) may result as a consequence of hyperphosphatemia and the trapping of calcium in injured muscles (Knochel, 1998). The expected parathyroid hormone-induced rise in 1,25 [(OH).sub.2] [D.sub.3] (active form of vitamin D, the principal regulator of intestinal calcium absorption) is blocked in the presence of renal failure (Bushinsky & Monk, 1998). Yet, as Bonventre et al. (1995) point out, the hypocalcemia is rarely symptomatic and should not be treated. Later in the course, as the muscle recovers from injury, the soft tissue calcification resorbs and contributes to the hypercalcemia observed during the diuretic (recovery) phase (Bonventre et al., 1995).

Hyperuricemia. Serum uric acid levels may exceed 40 mg/dl as a result of purines released from injured muscle that are converted to urate in the liver (Knochel, 1998). Hyperuricemia of this level is seldom seen in other conditions, including those caused by acute tumor lysis induced by chemotherapy (Bonventre, et al., 1995; Knochel, 1998).

Hypoalbuminemia and anemia. An ominous sign is hypoalbuminemia, which implies major capillary damage with leakage of albumin from the vascular space. Capillary damage can be so extensive that erythrocytes escape into interstitial tissues, which results in shock with an acute reduction in the hematocrit in the absence of bleeding or hemolysis (Knochel, 1998).

Hyperkalemia. Hyperkalemia is the most life-threatening consequence of rhabdomyolysis. Since more than 98% of potassium resides within cells, even a small area of skeletal muscle breakdown will release a large quantity of potassium, especially since skeletal muscle represents 60-70% of the total cellular mass (Bonventre et al., 1995). As Rombola and Baffle (1991) point out, if ARF accompanies the muscle cell breakdown, a persistent and severe hyperkalemia is almost always seen.

Sickle cell trait. Patients with sickle cell anemia or trait, or related S hemoglobinopathies, are at an increased risk for developing ARF secondary to rhabdomyolysis during periods of hypoxemia, hypotension, or acidosis that result from general anesthesia, severe sepsis, or strenuous physical exertion (Diederich, 1995). The presence of hemoglobin S (HbS) characterizes patients with sickle cell trait (SCT). HbS has a reduced affinity for oxygen that often leads to detrimental effects in SCT carriers during strenuous physical exercise (Gallais et al., 1996).

Collaborative Management

While numerous studies into the pathogenesis of exertional rhabdomyolysis have been done, considerable debate continues on exactly how to manage this condition. Everyone agrees that intervention early in the course of exertional-induced rhabdomyolysis is crucial.

Clinical reports suggest that volume expansion therapy may be effective in interrupting the course of ARF secondary to rhabdomyolysis (Bonventre et al., 1995). In severe cases of rhabdomyolysis, it is critical to correct hypovolemia and shock by the infusion of blood and crystalloids (Knochel, 1998). In less severe cases, vigorous intravenous (IV) fluid therapy with isotonic saline will help correct the hemoconcentration and intravascular volume depletion caused by the obligatory loss of plasma volume into the damaged tissue (Bonventre et al., 1995; Star, 1998). The severity of intravascular volume depletion is assessed by the blood pressure, physical examination, and the extent of hemoconcentration from an increase in hematocrit (Bonventre et al., 1995). With concomitant monitoring of the patient, infusion of isotonic normal saline at 200 to 300 ml/hr is done. Invasive monitoring in complex cases may be indicated (Bonventre et al., 1995).

Mannitol[R], although controversial, is advocated by many clinicians to improve renal perfusion and prevent intrarenal ferrihemate trapping. The renal vasodilating properties of mannitol and its inhibition of tubular reabsorption of glomerular filtrate increase the tubular pressure, which is believed to help flush out any obstructing casts (Bonventre et al., 1995). Mannitol is usually given in a single IV dose of 12.5 or 25 mg over 15 to 30 minutes along with sodium bicarbonate to alkalinize the urine (Knochel, 1998). Bonventre et al. (1995) refer to this as a "mannitol-bicarbonate cocktail," which consists of two ampules of mannitol and two ampules of sodium bicarbonate that are added to 800 ml of [D.sub.5] W infused at 250 ml/hour. An observable rise in urine flow rate should occur by the end of the 4-hour infusion. This regimen hastens the resolution of azotemia, helps correct the oliguria, and avoids the need for dialysis in approximately 50% of patients. However, if at the end of the 4-hour infusion there is no improvement, the patient has entered the established phase of oliguric ARF and is treated conservatively until dialysis can be arranged (Bonventre et al., 1995). While some clinicians advocate the use of mannitol and sodium bicarbonate from the onset, Bonventre and colleagues (1995) suggest starting the infusion only after the clinician has determined that no improvement in oliguria has occurred, despite a euvolemic state. In addition, as Knochel (1998) points out, this amount of mannitol infused into a total body water content of 40 liters results in only a trivial increase in plasma osmolarity, so its use must be clearly justifiable in increasing renal perfusion. Zager's (1996) study showed that while mannitol is a potent vasodilator, it might actually exacerbate rather than improve cellular energetics during the induction of ARF. If mannitol is infused immediately after renal ischemia, it will abruptly decrease renal cortical ATP levels, and in the presence of concomitant tubular damage, a worsening of cellular energy depletion can result (Zager, 1996). The rationale for sodium bicarbonate therapy lies in its ability to blunt the acidification of filtrate in the proximal tubule. This reduces the dissociation of filtered myoglobin into the ferrihemate compound, which causes tubular cell toxicity (Bonventre et al., 1995). The production of alkaline urine (pH of 7.0 or higher) also reduces the crystallization of uric acid that can further reduce tubular cell damage (Mallinson, Goldsmith, Higgins, Venning, & Ackrill, 1994). However, it is not always possible to achieve urinary alkalinization in some patients because of the severity of the associated metabolic acidosis (Knochel, 1998).

The administration of furosemide has been advocated to reduce sodium transport and oxygen utilization by the kidney, thus theoretically preserving energy stores in the renal tubular cells (Knochel, 1998). However, large doses of furosemide are ototoxic and large infusion volumes can cause pulmonary edema (Star, 1998). For this reason, furosemide should be given as a single trial in escalating doses; if the patient does not respond, it should not be readministered. Moreover, there is no solid evidence that furosemide alters the history of ARF (Star, 1998). IV furosemide, if administered, should be given slowly over 1 to 2 minutes. For IV infusion, furosemide should be diluted in [D.sub.5] W, 0.9% NaCl solution (isotonic saline) or Lactated Ringer's[R] solution. If high doses of furosemide are needed, it should be administered as a controlled infusion not to exceed 4 mg/minute (Truong, 1999).

If left untreated, hyperkalemia potentially causes dysrhythmias, decreased cardiac output, muscle paralysis, and respiratory failure. If rhabdomyolysis is severe, even modest hyperkalemia can be cardiotoxic because of the concomitant hypocalcemia that occurs. A serum potassium level of 6.5 mEq/L may be cardiotoxic when the serum calcium is profoundly decreased because calcium ions normally oppose the effects of potassium (Knochel, 1998). For this reason, the serum potassium level should not be relied upon as the sole marker for the severity of cardiotoxicity; rather, the electrocardiogram must be followed since electrocardiogram changes correlate with the level of potassium. While acute cardiotoxicity is most quickly and effectively treated with calcium chloride infusions, the calcium salts are rapidly deposited in injured tissues, making their effect transient. Reports have shown that simultaneous maneuvers to reduce the potassium concentration, such as glucose and insulin infusions and therapy with beta-sympathetic agonists, such as albuterol, are mandatory (Knochel, 1998). In addition, the efficacy of bicarbonate for the treatment of hyperkalemia has been questioned since injured muscle cells are less likely to take in potassium, making this therapy less effective (Knochel, 1998). A 20% sorbitol solution containing the sodium potassium exchange resin disodium polystyrene disulfonate (Kayexalate[R]) administered via the oral or rectal route helps blunt the rise of potassium over the next 2 to 3 days. In some cases, despite treatment, potassium ions are released at such a rapid rate from lysed cells that dialysis becomes mandatory (Knochel, 1998).

Although hypocalcemia is the usual problem in rhabdomyolysis, patients who receive large amounts of calcium salts intravenously along with the mobilization of calcium from injured tissue that occurs during the diuretic (recovery) phase of ATN (see Teaching Sidebar) can develop potentially fatal hypercalcemia (Knochel, 1998). Thus, Knochel (1998) and Gozal (1996) agree that calcium salts should not be used unless absolutely necessary. The increase in intracellular calcium concentration leads to stimulation of neutral protease and causes further cell destruction, so calcium is not administered for the treatment of hyperkalemia unless life-threatening dysrhythmias occur (Gozal, 1996). A study done by Lopez et al. (1995) showed that the administration of dantrolene, an inhibitor of calcium release from the sarcoplasmic reticulum, was associated with an improvement in clinical symptoms.

Hyperphosphatemia, if it occurs, is treated with phosphate binding antacids or with dialysis. An oral phosphate-binding agent, such as calcium carbonate or calcium hydroxide, will help correct hyperphosphatemia. The resultant decrease in the phosphate level will lead to a correction of hypocalcemia (Knochel, 1998).

The clinician must assess for the development of fascial compartment compression syndromes (Knochel, 1998; Szewczyk et al., 1998). While any muscle can be involved, it mostly involves the muscles of the lateral thigh, the gastrocnemius, the anterior tibial, and the gluteus maximus. Decomposition of protein components in muscle injury causes osmotic gradients that pull water into the muscle cell, and if the muscle is in a fascial compartment, the pressure increases and exceeds arterial pressure with resultant ischemia and necrosis (Knochel, 1998). Therefore, early recognition of elevation in intrafascial muscle compartment pressures is mandatory, not only for limb salvage but also to alleviate muscle injury and rhabdomyolysis (Knochel, 1998; Szewczyk et al., 1998). In patients who develop compartment syndrome, prophylactic treatment by fasciotomy has been shown to prevent secondary tissue necrosis (Knochel, 1998; Szewczyk et al., 1998). Ongoing investigations suggest that mannitol may be helpful in preventing compartment syndrome (Knochel, 1998).

Dialysis is indicated once ARF is established by the presence of azotemia and oliguria. Peritoneal dialysis is not an option in patients with exertional-induced ARF because of the inability of this regimen to clear solutes faster than they appear. Thus, hemodialysis is the preferred method of treatment (Bonventre et al., 1995). While several electrolyte imbalances may be present, hyperkalemia is a definite indication for dialysis. Other indications include acidosis, uremic encephalopathy, fluid overload, pulmonary edema, and acute congestive heart failure (Visweswaran & Guntupalli, 1999). Hemodialysis is often required daily for several days until the potassium level and rates of urea accumulation have fallen (Bonventre et al., 1995). The choice of dialysate used by the clinician is guided by electrolyte laboratory values. Although the blood flow and dialysate flow are independently determined by the clinician, it is important to keep in mind the possibility of excessive shifts in intravascular volume and electrolytes. Visweswaran & Guntupalli (1999) report that continuous renal replacement therapy by continuous venovenous hemofiltration-dialysis (CVVH-D) is effective in the treatment of electrolyte abnormalities and oliguric ARF; however, the effectiveness of this regimen in the management of rhabdomyolysis remains unclear.


Some patients will display mild renal dysfunction leading to a quick recovery, whereas others will require dialysis for periods up to 3 weeks. When patients enter the diuretic phase and their urine formation returns to normal with resolution of azotemia, dialysis can often be discontinued. The prognosis is good in most cases, with full recovery of renal function being the rule (Bonventre et al., 1995). Woodrow, Brownjohn, and Turney (1995) looked at rhabdomyolysis as the cause of ARF over a 14-year period (1980-1993) and reported a 78.6% survival rate.

Implications for Nurses

One of the most important things nurses can do is educate patients on ways to prevent rhabdomyolysis. It is imperative while obtaining histories to look for obvious clues that could lead to rhabdomyolysis. To help prevent exertional rhabdomyolysis in otherwise healthy patients who are prescribed an exercise regimen, advise them to not increase their workout more than 10% a week. When it is hot and humid, it is best to advise them to not increase their activity by this much. More importantly, advise them to drink plenty of fluids during exercise and to drink even more when it is hot and humid. Lastly, ensure that patients understand that seeking treatment immediately is key to preventing complications. Advise them to immediately go the hospital should they experience either severe muscle pain with swelling, weakness that will not go away, or dark urine after a long workout or serious injury (Visweswaran & Guntupalli, 1999).


Rhabdomyolysis is a potentially lethal syndrome with a broad spectrum of clinical and biochemical findings. The clinical signs and symptoms vary widely from myalgia to severe muscle weakness with involvement of other organ symptoms. The diagnosis is confirmed by measuring the serum creatine kinase and myoglobin serum levels. The major complications of rhabdomyolysis include ARF, compartment syndrome, and cardiac arrest. The treatment consists of maintaining an adequate circulating volume and diuresis to prevent renal complications. If treatment is initiated early enough in the acute phase, the prognosis is excellent.

Acknowledgment: The author would like to thank Patricia B. McCarley for her help in revising the posttest questions; and Dr. Larry Lancaster, Professor in the Acute Care Nurse Practitioner Program at Vanderbilt University School of Nursing, for his continual support in preparing this manuscript.


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Knochel, J.P. (1998). Pigment nephropathy. In A. Greenberg (Ed.), Primer on kidney diseases (2nd ed.) (pp. 273-276). Boston: Academic Press.

Lopez, J.R., Rojas, B., Gonzalez, M.A., & Terzic, A. (1995). Myoplasmic [Ca.sup.2+] concentration during exertional rhabdomyolysis. The Lancet, 345(8947), 424-425.

Mallinson, R.H., Goldsmith, D.J., Higgins, R.M., Venning, M.C., & Ackrill, P. (1994). Lesson of the week: Acute swollen legs due to rhabdomyolysis: Initial management as deep vein thrombosis may lead to acute renal failure. British Medical Journal, 309(6965), 1361-1362.

Nielsen, C., & Mazzone, P. (1999). Muscle pain after exercise. The Lancet, 353, 1062.

Rombola, G., & Batlle, D. (1991). Hyperkalemia. In H. Jacobson, G. Striker, & S. Klahr (Eds.), The principles and practice of nephrology (pp. 49-55). Philadelphia: B.C. Decker, Inc.

Singer, G.G. (1998). Fluid and electrolyte management. In C. Carey, H. Lee, & K. Woeltje (Eds.), The Washington manual of medical therapeutics (29th ed.) (pp. 55-60). Baltimore: Lippincott Williams & Wilkins.

Star, R.A. (1998). Treatment of acute renal failure. Kidney International, 54(6), 1817-1831.

Syrjala, J. Zvuori, J., Huttunen, K., & Vaananen, H.K. (1990). Carbonic anhydrase III as a marker for diagnosis of rhabdomyolysis. Clinical Chemistry, 36, 696.

Szewczyk, D., Ovadia, P., Abdullah, E, & Rabinovici, R. (1998). Pressure-induced rhabdomyolysis and acute renal failure. Journal of Trauma -- Injury Infection and Critical Care, 44(2), 384-388.

Toto, R.D. (1998). Approach to the patient with acute renal failure. In A. Greenberg (Ed.), Primer on kidney diseases (2nd ed.) (pp. 253-259). Boston: Academic Press.

Truong, L. (1999). Physician's drug handbook (8th ed.) Springhouse, PA: Springhouse Corp.

Visweswaran, P., & Guntupalli, J. (1999). Rhabdomyolysis. Critical Care Clinics, 15(2), 415-426.

Woodrow, G., Brownjohn, A.M., & Turney, J.H. (1995). The clinical and biochemical features of acute renal failure due to rhabdomyolysis. Renal Failure, 4, 467-474.

Zager, R.A. (1996). Rhabdomyolysis and myohemoglobinuric acute renal failure. Kidney International, 49(2), 314-326.


Acute renal failure related to exertional rhabdomyolysis is a medical condition that, if not diagnosed correctly and treated aggressively, can lead to serious dysfunction and may result in death. Although the history is invaluable in diagnosing this condition, it must be confirmed by laboratory testing. The sometimes subtle manifestations of exertional (non-traumatic) rhabdomyolysis make it mandatory that the health care team is able to recognize the signs and symptoms and understand the pathophysiology for prompt treatment and referral.


To discuss the pathophysiology, diagnostic approach, and management of patients with acute renal failure (ARF) related to rhabdomyolysis.


1. Describe the pathophysiology of rhabdomyolysis in patients with ARF.

2. Identify clinical and laboratory findings that aid in the diagnosis of ARF related to rhabdomyolysis.

3. Recognize the importance and basis for the various resources of collaborative management for patients with ARF related to rhabdomyolysis.


This offering for 2.5 contact hours is being provided by the American Nephrology Nurses' Association (ANNA), which is accredited as a provider and approver of continuing education in nursing by the American Nurses' Credentialing Center-Commission on Accreditation (ANCC-COA), This educational activity is approved by most states and specialty organizations that recognize the ANCC-COA accreditation process. ANNA is an approved provider of continuing education in nursing by the California Board of Registered Nursing, BRN Provider No. 00910; the Florida Board of Nursing, BRN Provider No. 27F0441; the Alabama Board of Nursing, BRN Provider No. P0324; and the Kansas State Board of Nursing, Provider No. LT0148-0738. This offering is accepted for RN and LPN relicensure in Kansas.

This article qualifies for the credit toward the 30 contact hours of fundamental nephrology nursing education required to take the CNN Examination effective January 1, 2000.

To receive continuing education credit, you must read the information in this article, complete and return the answer form on page 577 and appropriate fee to the ANNA National Office. Please refer to the answer form for the appropriate fee and address of the National Office.

RELATED ARTICLE: Teaching Sidebar

Syndrome of Acute Renal Failure

Prerenal azotemia: Renal blood flow decreases because of intense, compensatory renal afferent arteriolar constriction. Since renal plasma flow rate is the principal determinant of glomerular filtration rate (GFR), the filtration rate decreases markedly. Typically, there is an increased reabsorption of sodium and water that leads to concentrated urine with a low sodium concentration. Urea reabsorption is also increased, which leads to a disproportionate increase in the BUN: Creatinine ratio ([is greater than] 20:1) (Toto, 1998).

Intrarenal acute renal failure: The most common cause is acute tubular necrosis (ATN) due to ischemic or toxic insults. ATN leads to sloughing of tubular cells into the lumen that leads to partial or total obstruction of nephron flow, which contributes to a reduction in the GFR. The urinalysis reveals granular casts and renal tubular cells that indicate damaged tubules. Dilute urine with a high sodium concentration is typical because injured tubules do not normally transport solutes. This form of acute renal failure (ARF) may be accompanied by a predictable sequence of events -- an initiation phase (daily increase in serum creatinine and reduced urinary output); a maintenance phase (GFR relatively stable and urinary output may increase); and a recovery phase (serum creatinine decreases and tubule function is restored) (Toto, 1998).

Postrenal: Obstruction of the urinary tract at any level may cause ARF. This condition should be considered in any patient with acute anuria, especially those with a recent history of polyuria alternating with oliguria (Toto, 1998).

Troy A. Russell


Acute Renal Failure Related to Rhabdomyolysis: Pathophysiology, Diagnosis, and Collaborative Management

By Troy A. Russell

Posttest -- 2.5 Contact Hours Posttest Questions

(See posttest instructions on the answer form, next page) The Editor gratefully acknowledges Mary Cwiertniewicz for reviewing the questions in this CE posttest.

Case Scenario:

Mr. Black, 31 years old, has just completed an obstacle course and a 2-mile run as part of his required military regimen. Upon resting after the event, Mr. Black could not rise to a standing position. He was helped back to his barracks where subsequently his legs began to swell and he could not urinate. He was rushed to the emergency room where upon placement of a catheter, dark cola-colored urine was obtained. After questioning the patient regarding the precipitating event and obtaining necessary lab work, the clinician prepares to obtain the health history and perform the physical examination.
1. Since Mr. Black's suspected diagnoses
   include acute renal failure
  (ARF) related to rhabdomyolysis,
   it would be important to ask
   which question?

   A. What is your past medical history?
   B. What were you doing before the
      symptoms appeared?
   C. What did you eat for breakfast?
   D. What is your family history?

2. Mr. Black's ARF related to rhabdomyolysis
   is most likely caused by
   A. overhydration.
   B. overexertion.
   C. hemoglobin.
   D. malnourishment.

3. Based on the diagnosis of ARF
   related to rhabdomyolysis, Mr.
   Black's most likely chief complaint
   A. muscle pain.
   B. headache.
   C. backache.
   D. abdominal pain.

4. What findings in Mr. Black's urinalysis
   and microscopic urine examination
   indicate myoglobinuria?
   A. Negative benzidine reagent;
      [is less than] 5 RBCs per HPF
   B. 1+ on benzidine reagent; 5 RBCs
      per HPF
   C. 2+ benzidine reagent; 0 RBCs
      per HPF
   D. 4+ benzidine reagent; [is less than] 5 RBCs
      per HPF

5. Elevation of which laboratory test
   confirms Mr. Black's diagnosis of
   ARF related to rhabdomyolysis?
   B. CK-MM
   C. CK-BB
   D. CK-PP

6. Which of the following is characteristic
   of the autogenous phase
   in the pathophysiology of exertional
   A. Calcium activation
   B. Phospholipase depletion
   C. ATP depletion
   D. Protease activation

7. The nurse notes that Mr. Black's
   serum creatinine is disproportionately
   high compared to his blood
   urea nitrogen (BUN). This is based
   on his/her knowledge that the normal
   BUN:Creatinine ratio is
   A. 5:1.
   B. 10:1.
   C. 15:1.
   D. 20:1.

8. The significantly higher anion gap
   observed in patients with ARF related
   to rhabdomyolysis is thought to
   be caused by increased
   A. creatinine.
   B. organic acids.
   C. urea.
   D. potassium.

9. Which of the following is a proposed
   cause of damage to the renal
   tubular cells in rhabdomyolysis?
   A. Ferrihemate accumulation
   B. Excess enzymes
   C. Creatine dehydration
   D. Organic acid accumulation

10. During the diuretic (recovery)
   phase of acute tubular necrosis
   (ATN), the nurse is most likely to
   A. hypocalcemia.
   B. hypercalcemia.
   C. hypochloremia.
   D. hyperchloremia.

11. Based on which laboratory finding
   would the clinician suspect
   major capillary damage with leakage
   from the vascular space?
   A. Hyperphosphatemia
   B. Hypophosphatemia
   C. Hyperalbuminemia
   D. Hypoalbuminemia

12. The nurse places Mr. Black on a
   cardiac monitor in planning for
   which life-threatening consequence
   of rhabdomyolysis?
   A. Hypocalcemia
   B. Hyperalbuminemia
   C. Hyperkalemia
   D. Hypothyroidism

13. The nurse administers a mannitol-bicarbonate
   cocktail added to 800
   ml of DSW. He/she should expect an
   increase in Mr. Black's urinary output
   A. 1 hour.
   B. 2 hours.
   C. 3 hours.
   D. 4 hours.

14. A stat serum potassium level on
   Mr. Black is 7.0 mEq/L. Cardiotoxicity
   is most quickly and effectively
   treated with
   A. hemodialysis.
   B. glucose and insulin infusion.
   C. kayexalate.
   D. calcium chloride infusion.

15. Mr. Black's azotemia progresses
   to oliguria. Explanations to the
   patient should focus on which
   preferred method of treatment?
   A. Peritoneal dialysis
   B. Hemodialysis
   C. CRRT
   D. Plasmapheresis

16. Mr. Black asks you about his
   prognosis. Based on your knowledge
   of the diagnosis of ARF
   related to rhabdomyolysis, you
   feel comfortable telling him that
   A. "Full recovery of renal function is
   B. "He will be on dialysis for the rest
      of his life."
   C. "He should prepare a will and get
      his things in order."
   D. "He needs to ask the doctor."

Posttest Answer Grid Please circle your answer choice:
1.  a b c d
2.  a b c d
3.  a b c d
4.  a b c d
5.  a b c d
6.  a b c d
7.  a b c d
8.  a b c d
9.  a b c d
10. a b c d
11. a b c d
12. a b c d
13. a b c d
14. a b c d
15. a b c d
16. a b c d


Acute Renal Failure Related to Rhabdomyolysis: Pathophysiology, Diagnosis, and Collaborative Management

By Troy A. Russell

Posttest Instructions

* Select the best answer and circle the appropriate letter on the answer grid below.

* Complete the evaluation.

* Send only the answer form to the ANNA National Office; East Holly Avenue Box 56; Pitman, NJ 08071-0056.

* Enclose a check or money order payable to ANNA

* Posttests must be postmarked by December 20, 2002. If you receive a passing score of 70% or better, a certificate for 2.5 contact hours will be awarded by ANNA.

* Please allow 6-8 weeks for processing. You may submit multiple answer forms in one mailing, however, because of various processing procedures for each answer form, you may not receive all of your certificates returned in one mailing.

* This article qualifies for credit toward the 30 contact hours of fundamental nephrology nursing education required to take the CNN examination effective January 1, 2000. For further explanation, see the NNCC web site:

ANNA Member - $15 Non-Member- $25 Expiration Date -- (from membership card) Complete the Following
Name: --
Address: --
Telephone: --
ANNA Member --      -- Yes -- No           CNN       --Yes  --No
Source of Article: -- Journal   -- ANNA Web site (ANNAlink)

Note: If you wish to keep the journal intact, you may photocopy the answer sheet

Goal: To discuss the pathophysiology, diagnostic approach, and management of patients with acute renal failure related to rhabdomyolysis.
                                               Strongly    Strongly
Evaluation                                     disagree       agree
1. The objectives were related to the goal.
   a. Describe the pathophysiology of              1   2   3   4   5
   rhabdomyolysis in a patient with acute
   renal failure (ARF).
b. Identify clinical and laboratory findings       1   2   3   4   5
   that aid in the diagnosis of ARF related to
c. Recognize the importance and basis for the      1   2   3   4   5
   various resources of collaborative management
   for patients with ARF related to
2. The teaching/learning resources were            1   2   3   4   5
   effective to complete this activity.
3. A self-study format was effective for the       1   2   3   4   5
4. The On-Line format was effective.               1   2   3   4   5
   (if downloaded)
5. Minutes required to complete self-study,      50  75  100 125 150
   including the posttest

Comments --

Troy A. Russell, MSN, RN, ACPN, is an advanced practice nurse, VA Medical Center, Nashville, TN.
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Article Details
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Author:Russell, Troy A.
Publication:Nephrology Nursing Journal
Article Type:Statistical Data Included
Geographic Code:1USA
Date:Dec 1, 2000
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